Methamphetamine use disorders represent a significant and costly public health concern, yet efficacious pharmacotherapies for methamphetamine dependence remain elusive. Naltrexone, an FDA-approved opioid receptor antagonist with greatest affinity for the mu receptor, and to a lesser but meaningful extent kappa and delta receptors, represents a potentially efficacious medication for the treatment of methamphetamine dependence. Preclinical and clinical data suggest naltrexone is effective at reducing amphetamine craving; however, the neural mechanisms underlying this effect remain unknown. Furthermore, an individual's OPRM1 genotype, which encodes the mu-opioid receptor, may function to moderate naltrexone's effect on methamphetamine cue-induced craving. The overall objective of the proposed NRSA application is to foster my development as a clinical neuroscientist through the investigation of the neurobiological effects of naltrexone on methamphetamine cues in methamphetamine dependent individuals with and without the Asp40 variant of the OPRM1 gene. To do so, 15 individuals with methamphetamine dependence will be prospectively genotyped and undergo an fMRI protocol in which visual methamphetamine and control cues are presented. The participants will be scanned twice, once while on the target dose of naltrexone (50mg) and once on placebo. The data from these 15 participants will be combined with data acquired in an ongoing R21 by my sponsor (n = 15) for a final a sample of 30 methamphetamine dependent individuals. Whole-brain contrast analyses will identify the regions of activation associated with methamphetamine craving, while functional connectivity analyses will seek to discover pathways by which cue-induced craving is instated. OPRM1 genotype, as well as kappa and delta opioid receptor polymorphisms will be tested as moderators of neuroimaging response to naltrexone versus placebo. In addition, all analyses will control for medication altered cerebral blood flow using arterial spin labeling (ASL). The results of this translational project will advance medication development for methamphetamine dependence by assessing the pathways by which methamphetamine craving is instated and by testing whether naltrexone effectively targets these neural pathways.